Genetic polymorphism of the major regulatory element HS‐40 upstream of the human α‐globin gene cluster

The highly conserved 350‐bp major regulatory element HS‐40 (or αMRE) upstream of the human α‐globin gene cluster is involved in the regulation of α‐globin gene expression. The study of αMRE differences between human populations and the evolution of αMRE sequences in mammals may lead to a better unde...

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Bibliographic Details
Published in:British journal of haematology 2002-12, Vol.119 (3), p.848-854
Main Authors: Harteveld, Cornelis L., Muglia, Maria, Passarino, Giuseppe, Kielman, Menno F., Bernini, Luigi F.
Format: Article
Language:English
Subjects:
alpha-Thalassemia - genetics
Anemias. Hemoglobinopathies
Animals
Biological and medical sciences
Consensus Sequence - genetics
Continental Population Groups - genetics
Diseases of red blood cells
DNA - genetics
Genetic Linkage - genetics
Globins - genetics
haplotype
Haplotypes - genetics
Hematologic and hematopoietic diseases
Hominidae - genetics
Homozygote
HS‐40
Humans
major regulatory element
Medical sciences
Polymorphism, Genetic - genetics
population genetics
Regulatory Sequences, Nucleic Acid - genetics
Sequence Analysis, DNA
α‐globin gene cluster
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Summary:The highly conserved 350‐bp major regulatory element HS‐40 (or αMRE) upstream of the human α‐globin gene cluster is involved in the regulation of α‐globin gene expression. The study of αMRE differences between human populations and the evolution of αMRE sequences in mammals may lead to a better understanding of the function and importance of this element in the regulation of expression of the downstream α‐cluster. Denaturing gradient gel electrophoresis was used to determine the sequence heterogeneity of the αMRE region in 276 unrelated individuals, representing seven different populations. Furthermore, we analysed the α major regulatory elements of chimpanzee, orang‐utan and rhesus monkeys and compared them with the equivalent human and murine sequences. Six different αMRE haplotypes (labelled A to F) were found in humans. Haplotype frequencies between the seven populations showed a gradual shift to a higher haplotype A distribution from west to east, being the highest in Indonesians. The African sample shows the largest divergence in haplotypes. Five out of six different haplotypes were present, three of which were exclusively found in Africans. The high prevalence of the haplotype A in humans, together with the conservation of this haplotype in apes, suggests that it is the ancestral one. The αMRE fragment appears to be a highly polymorphic marker, which could be used in combination with the regular markers in the α‐cluster to extend the haplotype and to follow segregation of α‐thalassaemia genes in population studies more accurately.
ISSN:0007-1048
1365-2141
DOI:10.1046/j.1365-2141.2002.03917.x